The present invention relates to novel azabicyclic carbamates, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
More particularly the invention provides a compound of formula I 
wherein n is 1 or 2, R1, R2 and R3, independently, are hydrogen or (C1-4)alkyl and A is a group of formula 
wherein m is 1, 2 or 3, X is O, S, NH or CH2 and R4 and R5, independently, are hydrogen, halogen, hydroxy, (C1-4)alkyl, (C1-4)alkoxy, (C1-4)alkylthio, (C1-4)alkylamino, nitro, trifluoromethyl or phenyl, in free base or acid addition salt form.
Halogen denotes fluorine, bromine, chlorine or iodine.
Any alkyl, alkoxy and alkylthio groups are branched or straight chain groups. They are preferably methyl, methoxy or methylthio groups.
On account of the asymmetrical carbon atom(s) present in the compounds of formula I and their salts, the compounds may exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures including the racemic mixtures are part of the present invention.
In a further aspect, the invention provides a process for the production of the compounds of formula I and their salts, comprising the step of reacting a compound of formula II 
wherein n, R1 and R2 are as defined above, with a compound of formula III 
wherein R3 and A are as defined above, and N,Nxe2x80x2-carbonyldiimidazole or di(N-succinimidyl)carbonate, and recovering the resulting compound of formula I in free base or acid addition salt form.
According to a preferred embodiment, in a first step the compound of formula III is reacted with N,Nxe2x80x2-carbonyldiimidazole, and the resulting compound is reacted with the compound of formula II.
Alternatively, the compound of formula II can be reacted with a compound of formula IV 
wherein R3 and A are as defined above.
The reactions can be effected according to conventional methods, e.g. as described in the examples.
Working up the reaction mixtures according to the above processes and purification of the compounds thus obtained may be carried out in accordance to known procedures.
Acid addition salts may be produced from the free bases in known manner, and vice versa.
Compounds of formula I in optically pure form can be obtained from the corresponding racemates according to well-known procedures. Alternatively, optically pure starting materials can be used.
The starting materials of formula II, III and IV are known or may be obtained from known compounds, using conventional procedures.
Compounds of formula I and their pharmaceutically acceptable acid addition salts, hereinafter referred to as agents of the invention, exhibit valuable pharmacological properties when tested in vitro and in animals, and are therefore useful as pharmaceuticals.
In particular, the agents of the invention are xcex17 nicotinic acetylcholine receptor (nAChR) agonists.
In functional assays, the agents of the invention display high affinity at the xcex17 nAChR as shown in the following tests:
a) A functional assay for affinity at human xcex17 nAChR is carried out with a rat pituitary cell line stably expressing the human xcex17 nAChR. As a read out, the calcium influx upon stimulation of the receptor is used. In this assay, agents of the invention exhibit pEC50 values of about 5 to about 8.
b) To assess the activity of the agents of the invention on the human neuronal nAChR xcex14xcex22, a similar functional assay is carried out using a human epithelial cell line stable expressing the human xcex14xcex22 subtype. In this assay, agents of the invention show selectivity for the xcex17 nAChR subtypes.
c) To assess the activity of the compounds of the invention on the xe2x80x9cganglionic subtypexe2x80x9d and the muscle type of nicotinic receptor, similar functional assays as described under a) are carried out with a human epithelial cell line stably expressing the human ganglionic subtype or a cell line endogenously expressing the human muscle type of nicotinic receptors. In these assays, agents of the invention display no or little activity on the ganglionic and muscle type of nicotinic receptor subtypes.
In the model of mice showing sensory gating deficit (DBA/2-mice) described by S. Leonard et al. in Schizophrenia Bulletin 22, 431-445 (1996), the agents of the invention induce significant sensory gating at concentrations of about 10 to about 40 xcexcM.
The agents of the invention are therefore useful for the treatment of psychotic disorders such as schizophrenia, mania, depression and anxiety, and for the treatment of neurodegenerative disorders such as senile dementia, Alzheimer""s disease and other intellectual impairment disorders, such as attention deficit hyperactivity disorders (ADHD); Parkinson""s disease, Huntington""s chorea, amyotrophic lateral sclerosis and multiple sclerosis. The usefulness of xcex17 nAChR agonists in neurodegeneration is documented in the literature, e.g. in Wang et al., J. biol. Chem. 275, 5626-5632 (2000).
For the above-mentioned indications, the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.01 to about 100, preferably from about 0.1 to about 50 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 1 to about 500, preferably from about 5 to about 300 mg of an agent of the invention conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
The agent of the invention may be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.
The preferred compound is the stereoisomer of the (1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid 1-(2-fluorophenyl)-ethyl ester, the succinate of which has a melting point of 83-84xc2x0 C. and which has an optical rotation of +14.6xc2x0 (c=1; water, 20xc2x0 C., 589 nm), which is the compound of Example 61.
In accordance with the foregoing, the present invention also provides an agent of the invention, for use as a pharmaceutical, e.g. for the treatment of any condition mentioned above.
The present invention furthermore provides a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured in conventional manner. Unit dosage forms contain, for example, from about 0.25 to about 150, preferably from about 1 to about 25 mg of a compound according to the invention.
Moreover the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of any condition mentioned above.
In still a further aspect the present invention provides a method for the treatment of any condition mentioned above, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention.
The following examples illustrate the invention.